RheumatologyTier 2Disease (DEADMAN)

Myopathies - inflammatory

Description

Subtypes - serology now defines them better than histology

Subtype	Hallmark
Dermatomyositis	Rash + proximal weakness; perifascicular atrophy; complement/interferon-driven, perimysial
Polymyositis	A shrinking category - most reclassify as IMNM, ASS or IBM
Immune-mediated necrotising myopathy (IMNM)	Very high CK, few inflammatory cells, necrosis + regeneration; anti-SRP or anti-HMGCR
Antisynthetase syndrome	ILD + myositis + arthritis + mechanic's hands + Raynaud + fever; anti-Jo-1
Inclusion body myositis (IBM)	Older man, ASYMMETRIC, DISTAL finger flexors + quadriceps, dysphagia; treatment-refractory
Overlap myositis	With SLE, scleroderma, Sjogren, MCTD

Dermatomyositis skin signs

Heliotrope rash - violaceous periorbital, with oedema
Gottron papules (over MCP/PIP/DIP knuckles) and Gottron sign (extensor elbows/knees)
Shawl sign, V sign, holster sign - photodistributed poikiloderma
Mechanic's hands - cracked, hyperkeratotic radial fingers (antisynthetase)
Nailfold capillary dropout, dilated loops, ragged cuticles
Calcinosis cutis - especially juvenile DM
*Clinically amyopathic dermatomyositis - rash without weakness; still carries ILD and malignancy risk*

Epidemiology

Incidence ~1-2 per 100,000/yr; prevalence ~10-20 per 100,000
F>M ~2:1 (except IBM: M>F 2-3:1, age >50)
Bimodal age: juvenile DM (5-15), adult peak 45-60
Malignancy in up to 15-25% of adult dermatomyositis - highest in the 3 years either side of diagnosis
ILD in ~20-30% overall, up to 70-90% in antisynthetase syndrome

Aetiopathogenesis

Dermatomyositis - humoral/complement: MAC deposition on endomysial capillaries -> capillary dropout -> perifascicular ischaemia and atrophy
- Strong type I interferon signature
Polymyositis/IBM - CD8+ T cells invading non-necrotic MHC-I-expressing myofibres (cell-mediated)
IMNM - antibody-mediated necrosis; anti-SRP and anti-HMGCR; sparse inflammatory infiltrate
IBM - degenerative as well as inflammatory: rimmed vacuoles, congophilic inclusions, TDP-43 and p62 aggregates, mitochondrial (COX-negative, ragged red) change
Triggers: malignancy, drugs (statins, checkpoint inhibitors, hydroxyurea, D-penicillamine), viruses, UV exposure

Myositis antibodies - the most examinable table

Antibody	Phenotype
Anti-Jo-1 (and other tRNA synthetases: PL-7, PL-12, EJ, OJ)	Antisynthetase syndrome - ILD, arthritis, mechanic's hands, Raynaud, fever
Anti-Mi-2	Classic DM rash, good response to steroids, good prognosis, low malignancy risk
Anti-MDA5	*Clinically amyopathic DM + RAPIDLY PROGRESSIVE ILD - high mortality*; skin ulceration, palmar papules
Anti-TIF1-gamma (p155/140)	*Strongest MALIGNANCY association in adults*
Anti-NXP2	Malignancy; calcinosis, especially juvenile
Anti-SRP	IMNM - very high CK, severe weakness, cardiac involvement, refractory
Anti-HMGCR	Statin-associated IMNM
Anti-cN1A (NT5C1A)	Inclusion body myositis (also in Sjogren and SLE)

Diagnosis

Clinical

Symmetrical PROXIMAL weakness, progressive over weeks-months - stairs, hair-washing, rising from a chair
*Weakness, not pain - myalgia is present in only ~30%; prominent pain with normal power suggests fibromyalgia, PMR or statin myalgia*
Neck flexor weakness - characteristic
Dysphagia (pharyngeal/oesophageal striated muscle) -> aspiration risk - a red flag requiring urgent treatment
Dyspnoea (ILD, respiratory muscle), arthralgia, Raynaud, fever, weight loss

Bloods

CK raised - often >10x ULN; CK can be NORMAL in dermatomyositis, amyopathic DM and late IBM
Also raised: AST, ALT, LDH, aldolase - *"abnormal LFTs" in a weak patient are often muscle; check CK and GGT before a liver screen*
ANA positive in ~80%; a myositis-specific antibody in 30-40% (higher with extended myositis line blots)
ESR/CRP often normal - do not use to exclude

EMG

Short-duration, low-amplitude, polyphasic motor units (myopathic)
Fibrillations and positive sharp waves (irritative - active inflammation)
Guides the side to biopsy - biopsy the CONTRALATERAL muscle, since the needle itself causes inflammation

MRI

STIR: muscle oedema = active myositis -> targets the biopsy (patchy disease causes sampling error)
T1: fatty replacement and atrophy = chronic damage; also shows fibrosis and calcification
Useful to distinguish active inflammation (treat) from chronic damage (do not escalate)

Muscle biopsy

The diagnostic standard - especially to identify IBM and IMNM, which change management entirely
Perifascicular atrophy (DM), endomysial CD8 invasion (PM), necrosis without inflammation (IMNM), rimmed vacuoles (IBM)

Classification

2017 EULAR/ACR criteria - probability-based score using age of onset, weakness pattern, rash, dysphagia, CK, anti-Jo-1 and biopsy

Malignancy screening - mandatory in adult DM

CT chest/abdomen/pelvis, mammography, cervical screening, PSA, faecal occult blood/colonoscopy
Consider whole-body FDG-PET; transvaginal ultrasound + CA125 for ovarian cancer
*Repeat annually for 3 years, and re-screen with any relapse - highest yield with anti-TIF1-gamma and anti-NXP2*

ILD screening - mandatory in everyone

HRCT chest + PFTs (FVC, DLCO) at diagnosis, repeat if antisynthetase or anti-MDA5

Management

1. Induction

Prednisolone 0.75-1 mg/kg/day (up to 60-80 mg), or IV methylprednisolone pulses if severe (dysphagia, respiratory muscle, rapidly progressive ILD)
*Start a steroid-sparing agent at the same time, not after failure* - the steroid dose otherwise cannot be reduced
- Methotrexate (avoid if ILD - pneumonitis confuses the picture) or azathioprine
- Mycophenolate - preferred if ILD
- Ciclosporin or tacrolimus - especially anti-MDA5 rapidly progressive ILD
IVIG
- Approved for refractory dermatomyositis (ProDERM); first-line where dysphagia is severe, in pregnancy, or where infection precludes immunosuppression
- Particularly effective in anti-HMGCR IMNM - often added within 6 months of starting treatment
Rituximab - refractory DM/PM, antisynthetase, anti-SRP IMNM
Anti-MDA5 rapidly progressive ILD -> *triple therapy up front (steroid + calcineurin inhibitor + cyclophosphamide), +/- plasma exchange, +/- tofacitinib* - do not escalate stepwise; mortality is very high
Maintain immunosuppression for at least 2 years after remission before considering withdrawal

2. Non-drug - as important as the drugs

*Physiotherapy and graded exercise from the outset - the old advice to rest is wrong; exercise is safe and prevents disuse atrophy*
Speech pathology and swallow assessment if dysphagia; consider NG feeding
Sun protection and topical steroid/tacrolimus + hydroxychloroquine for DM rash (rash often persists after muscle remission)
- Hydroxychloroquine causes a drug eruption in ~30% of DM patients

3. Steroid-related and general care

Bone protection (calcium, vitamin D, bisphosphonate), PJP prophylaxis, gastroprotection, vaccination, glycaemic monitoring
*Distinguish relapse from STEROID MYOPATHY - steroid myopathy: painless, insidious, normal CK, no MRI oedema, improves on dose reduction*

4. Inclusion body myositis

*Does not respond to immunosuppression* - avoid prolonged steroid trials
Exercise, falls prevention, swallow management (cricopharyngeal dilatation/myotomy), aids and orthoses

5. Malignancy

Treating the tumour often improves the myositis - especially with anti-TIF1-gamma

Associations

Malignancy - ovarian, lung, breast, colorectal, gastric, pancreatic, nasopharyngeal (high in Asian populations); strongest with anti-TIF1-gamma
ILD - NSIP and OP patterns; antisynthetase and anti-MDA5
Other CTD overlap - scleroderma, SLE, Sjogren, MCTD, RA
Cardiac - myocarditis, conduction disease, arrhythmia (anti-SRP); a leading cause of death
Dysphagia and aspiration pneumonia
Calcinosis cutis - juvenile DM, anti-NXP2
Drugs - statins (IMNM), checkpoint inhibitors (often with myocarditis and myasthenia - a lethal triad), hydroxyurea, penicillamine
Raynaud phenomenon, arthritis, mechanic's hands

Natural history & complications

Most achieve remission or good control, but ~50% have residual weakness and many need long-term immunosuppression
5-year survival ~75-90%; worse with anti-MDA5 ILD, anti-SRP, cardiac involvement, dysphagia, older age, malignancy
Anti-Mi-2 has the best prognosis; anti-MDA5 rapidly progressive ILD the worst (6-month mortality up to 50%)
Inclusion body myositis: relentlessly progressive, most need a walking aid within 5-10 years; life expectancy near normal, but aspiration is the main risk
Death is from ILD, aspiration pneumonia, cardiac disease, malignancy and infection from immunosuppression - rarely from the muscle weakness itself
Monitor with power (MMT-8), functional measures and CK - CK lags and may stay raised after clinical remission; do not chase it

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